Alleviation mechanisms against hepatocyte oxidative stress in patients with chronic hepatic disorders

Autophagy induction and Mallory-Denk body (MDB) formation have been considered to have cytoprotective effects from cellular stress in liver diseases. We investigated the relations among oxidative stress, autophagy and MDB formation in patients with chronic hepatitis B (CHB), chronic hepatitis C (CHC) and non-alcoholic fatty liver disease (NAFLD) to clarify the alleviation mechanisms against oxidative stress of hepatocytes.

First, we treated cultured cells with proteasome inhibitor (PI) or free fatty acid (FFA) and evaluated endoplasmic reticulum (ER) stress, oxidative stress, ubiquitinated proteins and p62 by western blotting. Then, we used human liver biopsy samples to evaluate oxidative stress, autophagy and MDB formation by immunohistochemical analysis.

Treatment with PI or FFA increased ER stress, oxidative stress, ubiquitinated proteins and p62 in cultured cells. Human liver biopsy samples of CHC and NAFLD showed that MDB formed in areas with strong oxidative stress and that the MDB-containing cells circumvented oxidative stress. Keratin 8 (K8) expression was strong in MDB-containing cells in CHC and NAFLD. However, in CHB samples, the expression of K8 was not increased in response to oxidative stress and MDB aggregates did not appear. Aminotransferase values were significantly lower in patients with CHC and NAFLD in whom light chain 3 antibody expression was increased in response to oxidative stress.

Strong expression of K8 was considered to be important for MDB formation. MDB protect liver cells from oxidative stress at a cellular level and autophagy reduced hepatic damage when it was induced in the hepatocytes exposed to strong oxidative stress.